Drug abuse has almost become a way of life to a rapidly growing segment of the world population, for example in the United States and Canada. It has become the vogue of many of the younger generation to experiment with any type of drug that will produce an emotional, psychological, euphoric, depressive or generally psychedelic experience.
A major problem is the abuse of medicinal opioid formulations by the parenteral route.
Another route of abuse which has become of serious concern is snorting of fine powder obtained from crushed opiod dosage form or the oral ingestion of finely crushed extended release oral dosage form in order to instantaneously obtain the benefit of the total opiod present in the slow release dosage form.
Another phenomenon that has become of concern regarding the use of extended release opiod analgesics is the discovery that they dose dump in the presence of alcohol and release all their content at once.
There has been a lot of concern with regards to the performance of extended release narcotics taught in prior art and currently commercialized. This is because the extended release or controlled release mechanism of current extended release opiod agonists using compositions and methods taught in the prior art is compromised and destroyed in the presence of alcohol leading to the loss of controlled release effects and complete release or dose dumping of its opiod content.
The danger and economic consequences of dose dumping in the presence of alcohol for current controlled release narcotic analgesics was highlighted when in Jul. 14, 2005 Purdue Pharma voluntarily took its pain-relieving narcotic analgesic Palladone (hydromorphone hydrochloride) capsules off the market. The company took the action on July 13 following an FDA request to withdraw Palladone because of safety concerns. The FDA approved Palladone in September 2004. The drug was launched by Purdue Pharma in February 2005. Palladone was approved for the management of persistent, moderate-to-severe pain in patients requiring continuous, around-the-clock pain relief with a high-potency opioid for an extended period of time. An FDA news release stated that serious and potentially fatal adverse reactions can occur when Palladone extended release capsules are taken together with alcohol.
According to an FDA news release, Palladone is a once-a-day pain management drug containing a very potent narcotic. New data gathered from a company-sponsored study testing the potential effects of alcohol use shows that when Palladone is taken with alcohol the extended release mechanism is harmed which can lead to dose-dumping. The FDA described dose-dumping, as the rapid release of the drug's active ingredient into the bloodstream. The agency's news release pointed out that dose-dumping, even with a low dose of Palladone (12 milligrams), could lead to “serious, or even fatal, adverse events in some patients”. The FDA also warned that the risk increases for higher doses of Palladone.
Health Canada also issued an Advisory to warn of serious health risks associated with the consumption of alcohol while taking any slow-release opioid analgesics, following data from Purdue Pharma.
It can be argued that just like in the case of Palladone all powerful pain management drugs such as opiod agonists or narcotic analgesics have serious risks if used incorrectly, and this is particularly true for the current extended release formulations in the prior art or under commercialization. In fact Health Canada has advised patients receiving other slow-release opioids to be aware that these products may react in a similar way to hydromorphone slow release formulation when co-ingested with alcohol i.e., they may be released into the blood quickly (dose-dumping) instead of over extended release time periods, for example 24 hours.
This situation continues to present an unacceptably high level of patient risk. There is a great concern that as more patients take current compostions, safety problems will arise since even having one alcoholic drink could have fatal implications. The use of patient information vial label warnings regarding the dangers of using opioids and alcohol concomitantly is not expected to solve this problem. As a matter of fact the FDA has said that the agency doesn't believe that “potentially fatal, adverse events can be effectively managed by label warnings alone. . . . ”
Health authorities have turned up the heat and are demanding the pharmaceutical companies come clean and put interests of patients first. Accordingly, to investigate if the same effect occurs with other slow-release drugs, Health Canada requests that all manufacturers of these products provide information on the interaction between their drug and alcohol; if this is not possible, studies investigating product interactions with alcohol are to be conducted and completed within six months. Health Canada states that the data will be assessed within a three-month period and that further action will be taken if required.
From the foregoing there is therefore an urgent and great need for compositions of opiod agonist or narcotic analgesics or abuse-able substances which have a reduced potential for abuse or dose-dumping in the presence of alcohol.
Attempts have been made in the past to control the abuse potential associated with opioid analgesics. Parenteral dose of opioid analgesics are more potent as compared to the same dose administered orally. Therefore, drug abuse is often carried out by the extraction of the opioid from the dosage form, and the subsequent injection of the opioid (using any “suitable” vehicle for injection) in order to achieve a “high.” Attempts to curtail abuse have therefore typically centered around the inclusion in the oral dosage form of an opioid antagonist which is not orally active but which will substantially block the analgesic effects of the opioid if one attempts to dissolve the opioid and administer it parenterally.
U.S. Pat. No. 3,254,088, describes the preparation of naloxone and its activity as a narcotic antagonist.
U.S. Pat. No. 3,493,657, describes the combination of morphine and naloxone as a composition for parenteral use “which has a strong analgesic, as well as antagonistic effect, without the occurrence of undesired or dangerous side effects.”
A New York Times article appearing in a Jul. 14, 1970 issue described the oral administration of naloxone to narcotic addicts as a method of treatment. The oral administration of naloxone (in high doses) “makes it impossible for the addict to experience a high no matter how much heroin he uses.”
The combination of pentazocine and naloxone has been utilized in tablets available in the United States, commercially available as Talwin® from Sanofi-Winthrop. Talwin® contains pentazocine hydrochloride equivalent to 50 mg base and naloxone hydrochloride equivalent to 0.5 mg base. Talwin® is indicated for the relief of moderate to severe pain. The amount of naloxone present in this combination has no action when taken orally, and will not interfere with the pharmacologic action of pentazocine. However, this amount of naloxone given by injection has profound antagonistic action to narcotic analgesics. Thus, the inclusion of naloxone is intended to curb a form of abuse of oral pentazocine which occurs when the dosage form is solubilized and injected. Therefore, this dosage has lower potential for parenteral abuse than previous oral pentazocine formulations. However, it is still subject to patient misuse and abuse by the oral route, for example, by the patient taking multiple doses at once.
Sunshine, et al. “Analgesic Efficacy of Pentazocine Versus a Pentazocine-Naloxone Combination Following Oral Administration”, Clin. J. Pain, 1988:4:35-40, reported on the effect of the addition of 0.5 mg naloxone on the analgesic efficacy of pentazocine 50 mg. The combination was found to be significantly less efficacious than pentazocine for the sum of the pain intensity difference (SPID), and for relief and pain intensity difference (PID) at the fourth hour. For patients with moderate baseline pain, the combination produced significantly less pain relief than pentazocine for SPID and for relief and PID at hours 3 and 4. In patients with severe baseline pain, there was no significant difference found between pentazocine and the combination of pentazocine plus naloxone.
Wang, et al. “Crossover and Parallel Study of Oral Analgesics”, J. Clin Pharmacol 1981; 21:162-8, studied the combination of naloxone 0.25 mg and Percodan® (composed of 4.5 mg oxycodone HC1, oxycodone terephthalate 0.28 mg, aspirin 224 mg, phenacetin 160 mg, and caffeine 32 mg) compared to Percodan® alone, and placebo in a crossover study of patients with chronic pain. The combination had lower mean scores than Percodan® alone for most of the analgesic hourly parameters in the later hours of the trial. However, for the summary variables, the combination showed no significant difference from either placebo or Percodan®.
A fixed combination of buprenorphine and naloxone was introduced in 1991 in New Zealand (Temgesic®, Reckitt & Colman) for the treatment of pain.
A fixed combination therapy comprising tilidine (50 mg) and naloxone (4 mg) has been available in Germany for the management of severe pain since 1978 (Valoron®, Goedecke). The rationale for the combination of these drugs is effective pain relief and the prevention of tilidine addiction through naloxone-induced antagonisms at the morphine receptor.
U.S. Pat. No. 3,773,955 (Pachter, et al.) described orally effective analgesic compositions which upon parenteral administration do not produce analgesia, euphoria, or physical dependence, and thereby prevent parenteral abuse of the analgetic agents. Such compositions contained from about 0.1 mg to about 10 mg naloxone per analgetic oral dose. This reference was not concerned with oral abuse of opioids.
U.S. Pat. No. 3,493,657 (Lewenstein, et al.) described compositions comprising naloxone and morphine or oxymorphone, which compositions were said to provide a strong analgesic effect without the occurrence of undesired side effects such as hallucinations.
U.S. Pat. No. 4,457,933 (Gordon, et al.) described a method for decreasing both the oral and parenteral abuse potential of strong analgesic agents such as oxycodone, propoxyphene and pentazocine, by combining an analgesic dose of the opioid with naloxone in a specific, relatively narrow range. Oxycodone-naloxone compositions having a ratio of 2.5-5:1 parts by weight and pentazocine-naloxone compositions having a ratio of 16-50:1 parts by weight were preferred. The dose of naloxone which was to be combined with the opioid is stated to substantially eliminate the possibility of either oral or parenteral abuse of the opioid without substantially affecting the oral analgesic activity thereof.
U.S. Pat. No. 4,582,835 (Lewis) describes a method of treating pain by administering a sublingually effective dose of buprenorphine with naloxone. Lewis describes dosage ratios of naloxone to buprenorphine from 1:3 to 1:1 for parenteral administration, and from 1:2 to 2:1 for sublingual administration.
U.S. Pat. No. 6,627,635 teaches a method of preventing abuse of opioid dosage forms wherein an analgesically effective amount of an orally active opioid agonist is combined with an opioid antagonist into an oral dosage form which would require at least a two-step extraction process to be separated from the opioid agonist, the amount of opioid antagonist including being sufficient to counteract opioid effects if extracted together with the opioid agonist and administered parenterally.
U.S. Pat. No. 6,696,088 discloses tamper-resistant oral opioid agonist formulations comprising (i) an opioid agonist in releasable form and (ii) a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact, such that the ratio of the amount of antagonist released from said dosage form after tampering to the amount of said antagonist released from said intact dosage form is about 4:1 or greater, wherein said agonist and antagonist are interdispersed and are not isolated from each other in two distinct layers.
Despite all the above attempts in the prior art to address the problem of drug abuse, the problem persists partly because of design faults in the compositions and the addicts coming up with creative ways to beat the anti drug abuse mechanism. At present the problem is escalating at an alarming rate with devastating financial and social consequences.
Therefore, there is still a need to develop a stable drug delivery device that can be reproducibly manufactured and have a desired effect of reducing potential for abuse.